Objective: To estimate the economic burden of hemophilia A and B in the patients referred to the related referral hospital in the south of Iran in 2017. Methods: This cross-sectional study was a partial economic evaluation and a cost of illness study, carried out in 2017. All the patients with hemophilia A and B referred to the related hospital affiliated to Shiraz University of Medical Sciences in the south of Iran were included in the study (N = n = 253). A data collection form was used to collect the required data, including patients' direct and indirect costs. Results: The mean annual cost was 36028 USD. The mean costs per patient with hemophilia A and B were 37661 USD and 30775 USD, respectively, in which the greatest part were related to direct medical costs (98.32% in hemophilia A, 98.18% in hemophilia B, and 98.29% of the total costs), and the cost of clotting factor concentrates accounted for the largest share of the patients' direct medical costs. Also, considering the number of hemophilia patients in Iran, the mean annual cost of the patients in 2017 was 414480325 USD, of which 381503701 USD was for hemophilia A and 32976624 USD was for hemophilia B patients. Conclusion: Considering the significant economic burden of hemophilia and in order to reduce the costs, the following suggestions can be offered: provision of clotting factor concentrates domestically in accordance with the world standards, and providing specialized services and care to hemophilia patients in towns.